The Carolina Breast Cancer Study (CBCS) is a comprehensive, interdisciplinary investigation into the causes of breast cancer in African American and white women. CBCS focuses on understanding how genetic and environmental factors interact to cause breast cancer. From 1993-2001, CBCS enrolled 2311 cases of in- situ and invasive breast cancer and 2022 frequency-matched controls from a defined geographic region of eastern and central North Carolina. 40% of CBCS participants are African-American. Over 70 peer-review publications have resulted. During the last SPORE funding cycle (2001-2006), we used previously collected DMA samples to conduct genotyping for polymorphisms in DMA repair genes. Genotypes at multiple genetic loci were combined to create "pathway" genotypes. We observed interactions between combinations of single nucleotide polymorphisms (SNPs) in the double strand break DNA repair pathway and radiation exposure, and combined genotypes in the nucleotide excision DNA repair pathway and smoking. The data rich CBCS attracted biostatistics collaborators who developed statistical methods to estimate haplotypes at the individual level and to use haplotypes to evaluate gene-gene and gene-environment interactions. We propose to expand our previous investigations by conducting a comprehensive study of haplotypes in genes involved in DNA repair, damage recognition, cell cycle control and cellular proliferation, hormone biosynthesis and metabolism, and oxidative metabolism. The advent of multiplex genotyping and identification of haplotype-tagging SNPs now makes it possible to capture the principal sources of genetic variation in the candidate genes in African Americans and whites. With newly-developed statistical methods, haplotypes will be used to evaluate gene-gene as well as gene-environment interactions. Monte Carlo simulation and applied Bayesian analysis will be used to address multiple hypothesis testing. We will also genotype 100 SNPs that serve as ancestry informative markers in order to adjust for population stratification. We used tumor blocks from CBCS cases to determine the prevalence of specific subtypes of breast cancer. The subtypes were codified using gene expression profiling. In the CBCS, the estrogen-receptor positive forms of breast cancer, Luminal A and B, were found at highest frequency in white women and older African American women, while the estrogen-receptor negative forms, including Basal-like breast cancer, were at highest frequency in younger African American women. CBCS patients with Basal-like breast cancer had lower disease-specific survival than patients with Luminal A or B. Our preliminary data suggest that combinations of genetic and environmental exposures lead to increased risk of specific subtypes of breast cancer. We will expand our investigation of genetic susceptibility to candidate genes for breast cancer subtypes, including newly-discovered polymorphisms in genes that show differential expression in breast cancer subtypes. Positive findings (including main effects and associations with breast cancer subtypes) will be repeated using DNA samples collected from a large population-based study in Norway.